Finding Sleeping Beauty: T Cell Biosensors for Dormant Cancer Detection

寻找睡美人：用于检测休眠癌症的 T 细胞生物传感器

• 批准号: 10487754
• 负责人: Gabriel A Kwong
• 金额: $ 110.74万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10487754
• 关键词: Antibodies; Antigens; Binding; Biological Markers; Biosensor; Blood; Bone Marrow; Breast Cancer Patient; Cancer Detection; Cells; Clinical; Disease; Engineering; Estrogen receptor positive; Future; Genetic; Growth; In complete remission; Lead; Libraries; Life; Lung; Malignant Neoplasms; Medicine; Memory; Meta-Analysis; Methods; Monitor; Neoplasm Metastasis; No Evidence of Disease; Patients; Peptide Hydrolases; Peptides; Phenotype; Proteolysis; Recurrence; Relapse; Relative Risks; Reporting; Risk; Sensitivity and Specificity; Site; Sleeping Beauty; Symptoms; T cell therapy; T-Cell Activation; T-Lymphocyte; Therapeutic Intervention; Tumor Antigens; Urine; angiogenesis; cancer immunotherapy; cancer type; design; engineered T cells; extracellular; hormone therapy; imaging detection; in vivo; malignant breast neoplasm; neoplastic cell; receptor; screening; sensor; treatment response; tumor

PROJECT SUMMARY Some types of cancers, as exemplified by estrogen receptor positive breast cancer, can recur as metastatic disease many years or even decades following a dormancy period where the patient displays no clinical symptoms. Late recurrence is thought to arise from disseminated tumor cells (DTCs) that were not killed by initial treatment and that lie dormant at metastatic sites such as the bone marrow until they reawaken. Strikingly, meta- analysis of over 60,000 early-stage ER-positive breast cancer patients treated with endocrine therapy revealed that the relative risk of recurrence progressively increases over a period of at least 20 years, indicating that patients in complete remission with no evidence of disease could harbor dormant cancer and remain at risk of metastatic relapse for the remainder of their life. Currently, there is no widely used method to monitor the dormant state nor its reawakening. The arrival of cancer immunotherapy has revealed exciting possibilities using engineered T cells as living medicines. T cells designed with tumor-targeting receptors and sophisticated genetic circuits have led to striking treatment responses in patients with certain types of cancers that were previously untreatable. This moment is an opportunity to not only build a future where T cells are engineered as therapies, but also as living sensors that can detect cancer with sensitivities and specificities beyond what is currently possible. The activation and growth of dormant tumor cells into micro-metastases require the hallmark expression of proteases during key steps such as angiogenesis. To exploit protease dysregulation, this project will develop engineered receptors that sense proteolysis to detect reawakening. These contain an extracellular single chain antibody that is blocked by a peptide mimotope such that they can bind to their cognate antigens only after the blocking peptide is removed by proteolysis, restricting T cell activation to the specific condition where the cognate protease and tumor antigen are both present. Following activation, T cell sensors amplify the release of synthetic biomarkers (blood, urine and imaging) for detection. Genetically encoded libraries (>10^4) of protease-activatable receptors will allow in vivo screening of 1000s of candidate T cell sensors to positively and negatively select for constructs that can report on awakening in different microenvironments such as the bone marrow and lungs. The adoptive transfer of T cell sensors with memory phenotype could lead to life-long T cell sensors that continuously monitor for future disease. These technological breakthroughs will have huge implications in understanding how and when dormant cells reawaken and guide therapeutic interventions at the earliest stages of reactivation.

项目概要 某些类型的癌症，例如雌激素受体阳性乳腺癌，可能会复发为转移性癌症 在患者没有表现出任何临床症状的休眠期后许多年甚至几十年的疾病 症状。晚期复发被认为是由未被初始治疗杀死的播散性肿瘤细胞 (DTC) 引起的。 治疗后，它们会在骨髓等转移部位处于休眠状态，直到它们重新苏醒。引人注目的是，元 对 60,000 多名接受内分泌治疗的早期 ER 阳性乳腺癌患者的分析显示 复发的相对风险在至少 20 年的时间内逐渐增加，这表明 完全缓解但没有疾病证据的患者可能患有休眠癌症并仍然面临罹患癌症的风险 在他们的余生中转移复发。目前，还没有广泛使用的方法来监测休眠状态 状态及其重新唤醒。癌症免疫疗法的到来揭示了令人兴奋的可能性 工程化 T 细胞作为活体药物。 T 细胞设计有肿瘤靶向受体和复杂的遗传 电路对患有某些类型癌症的患者产生了惊人的治疗反应，而这些癌症以前是 无法治疗的。这一刻是一个机会，不仅可以构建 T 细胞被设计为疗法的未来， 而且还可以作为活体传感器来检测癌症，其灵敏度和特异性超出了目前的水平 可能的。休眠肿瘤细胞的激活和生长为微转移需要标志 蛋白酶在血管生成等关键步骤中的表达。为了利用蛋白酶失调，该项目 将开发出感知蛋白水解作用的工程受体来检测重新唤醒。它们含有一种细胞外 被肽模拟表位封闭的单链抗体，以便它们可以与其同源抗原结合 仅在通过蛋白水解去除阻断肽后，将 T 细胞激活限制在特定条件下 其中同时存在同源蛋白酶和肿瘤抗原。激活后，T 细胞传感器会放大 释放合成生物标志物（血液、尿液和成像）进行检测。遗传编码文库 (>10^4) 蛋白酶激活受体的研究将允许体内筛选数千个候选 T 细胞传感器，以积极地 并负面选择可以报告不同微环境（例如 骨髓和肺。具有记忆表型的 T 细胞传感器的过继转移可能会导致终生 T 细胞传感器持续监测未来的疾病。这些技术突破将产生巨大的影响 了解休眠细胞如何以及何时重新唤醒并指导治疗干预的意义 重新激活的最早阶段。